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ClinicalTrials.gov Identifier: NCT01222247

Recruitment Status
:
Active, not recruiting

First Posted
: October 18, 2010

Last Update Posted
: January 10, 2018

Sponsor:

The George Washington University Biostatistics Center

Collaborators:

National Heart, Lung, and Blood Institute (NHLBI)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Infants born between 34 and 36 weeks of gestation, known as 'late preterm', are more likely to be admitted to a special care nursery, and more likely to suffer respiratory complications than infants born at term. The use of antenatal corticosteroids has been shown to improve lung function in very premature infants, but has not been evaluated in those likely to deliver in the late preterm period.

This research study will attempt to answer the following primary research question: Do steroids, compared to no steroids, decrease babies' need for oxygen support when given to pregnant women at least 12 to 24 hours before they deliver at 34 weeks to 36 weeks gestation? The research study will also collect information on whether steroids improve the chances that the baby will not get sick from other causes.

The rate of preterm birth has steadily increased in the United States over the past 10 years. This increase is driven in part by the rising rate of late preterm birth, defined as those births occurring between 34 and 36 weeks. Late preterm infants experience a higher rate of readmission than their term counterparts, and these infants are more likely to suffer complications such as respiratory distress, kernicterus, feeding difficulties, and hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared to term infants. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period. If shown to reduce the need for respiratory support and thus to decrease the rate of special care nursery admissions and improve short-term outcomes, the public health and economic impact will be considerate.This protocol describes a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of neonatal intensive care unit (NICU) admissions and improving short-term outcomes in the late preterm infant.

Two follow-up studies will be conducted concurrently. The first follow-up study will examine if the positive effects of betamethasone on lung function will persist in children at 6 years of age of mothers randomized to betamethasone with an expected late preterm delivery. Neonatal respiratory morbidity is associated with an increased risk of adverse childhood respiratory disease. Thus it is quite plausible that the effect of betamethasone, in reducing neonatal morbidity, particularly TTN, will translate into improved respiratory morbidity in early childhood.The primary outcome is childhood respiratory disease defined by a composite outcome of abnormal pulmonary function test (PFT) measured by spirometry, physician diagnosis of asthma, or other respiratory illnesses with medication.

The second follow-up study will examine whether late preterm antenatal betamethasone treatment is associated with long-term neurocognitive functioning, and whether there are any long-term consequences of what is believed to be transient neonatal hypoglycemia. Cognitive function will be measured by the Differential Ability Scales 2nd Edition (DAS-II) core components of the general conceptual ability (GCA) that includes verbal ability, non-verbal reasoning ability and spatial ability. The primary outcome is defined as a GCA score of <85 (1 standard deviation below the mean) at 6 years of age or greater.

The active study drug, betamethasone. 3 mg per ml betamethasone sodium phosphate 3 mg per milliliter betamethasone acetate The first dose of study drug medication will be administered at randomization as 2 ml injection; the next dose of 2 ml will be administered 24 hours later.

Other Name: Corticosteroid

Placebo Comparator: Placebo

A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart

Need for respiratory support: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 2 hours or more in the first 72 hours, or fraction of inspired oxygen (FiO2) greater than or equal to 0.30 for 4 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth, or neonatal death less than 72 hours of age

Secondary Outcome Measures
:

Maternal outcomes [ Time Frame: Delivery ]

Chorioamnionitis, Postpartum endometritis, delivery prior to steroids completion, time in hours from initial dose to delivery, length of labor, mode of delivery, indication for delivery, length of stay

Neonatal morbidity / mortality [ Time Frame: 72 hours of life ]

Major respiratory morbidity: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 12 hours or more in the first 72 hours, or FiO2 greater than or equal to 0.30 for 24 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth or neonatal death less than 72 hours of age

Respiratory Distress Syndrome [ Time Frame: Delivery ]

Respiratory distress defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis) with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates

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Ages Eligible for Study:

Child, Adult, Senior

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Singleton Pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14,0 weeks by project gestational age is acceptable

Gestational age at randomization between 34,0weeks and 36,5 weeks confirmed by study criteria

High probability of delivery in the late preterm period (any one of the following):

Membrane rupture as defined by the occurrence of any two of the following: pooling of fluid in the vaginal vault, positive Nitrazine test, ferning of vaginal fluid, positive AmniSure test; or any one of the following: indigo carmine pooling in the vagina after amnioinfustion, visible leakage of amniotic fluid from the cervix

or

Preterm labor with intact membranes. Preterm labor is defined as at least 6 regular uterine contractions in an observation period of no more than 60 minutes and at least one of the following: cervix greater than or equal to 3cm dilated or at least 75% effaced

or

Planned delivery by induction of labor or cesarean section in no less than 24 hours and no more than 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36,5 weeks at the latest, whereas a cesarean delivery must be scheduled by 36,6 weeks at the latest. Therefore the latest gestational age for randomization is 36,4 weeks for a planned induction. The planned delivery may be for any indication, such as the following: prior myomectomy, prior classical cesarean, intrauterine growth restriction (IUGR), oligohydramnios, preeclampsia, nonreassuring fetal heart rate tracing warranting delivery, abruption, placenta previa

Exclusion Criteria:

Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group

Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group

Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically

Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops

Maternal contraindication to betamethasone: hypersensitivity reaction to any components of the medication, idiopathic thromboycytopenic purpura, systemal fungal infection in case of exacerbation by betamethasone, use of amphotericin B due to the possibility of heart failure with concomitant betamethasone

Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy

Delivery expected within 12 hours of randomization, because of insufficient time of corticosteroids to confer benefit, including any of the following:

A. Rupture of Membranes (ROM) does not satisfy protocol criteria - exclude if the patient being evaluated for Preterm Premature Rupture of Membranes (pPROM), does not have preterm labor or planned delivery and does not satisfy the spontaneous membrane rupture criteria (any 2 of: positive Nitrazine test, pooling of fluid in the vaginal vault test or ferning of vaginal fluid; or indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix) B. Rupture of the membranes in the presence of more than 6 contractions per hour or cervical dilation of 3 cm or more, unless oxytocin was withheld for at least 12 hours (other induction agents allowed) C. Chorioamnionitis - exclude if patient is diagnosed with chorioamnionitis D. Cervical dilation ≥ 8 cm E. Evidence of non-reassuring fetal status requiring immediate delivery

Participation in another interventional study that influences neonatal morbidity and mortality

Participation in this trial in a previous pregnancy

Delivery at a non-network hospital

At 36, 0 weeks to 36, 5 weeks and quota for 36 weeks already met. To ensure there is an adequate proportion of women presenting at 34 to 35 weeks of gestation, enrollment will be restricted so that no more than 50% of the women in the trial present at 36 weeks.

No ultrasound < 20 weeks for unsure last menstrual period (LMP). If the patient has an unsure LMP but she had no dating ultrasound before 20 weeks by ultrasound parameters, she is excluded.

No ultrasound < 24 weeks for sure LMP. If the patient has an sure LMP but she had no dating ultrasound before 24 weeks by ultrasound parameters, she is excluded

Multifetal gestation. Exclude if current multifetal gestation or a single gestation resulting from a reduction of a multiple of higher order than twins